title: Initial exploration of oral pazopanib in healthy participants and patients with age-related macular degeneration.
abstract: OBJECTIVE
  Neovascular age-related macular degeneration (AMD) is managed with intravitreal anti-vascular endothelial growth factor therapy; however, the burden of care is high and alternate approaches could be beneficial. OBJECTIVE To identify an acceptable dose of oral pazopanib for investigation in AMD.
  
  
  METHODS
  Fourteen-day, placebo-controlled, dose-rising study in 72 healthy participants and 28-day phase 2a open-label study in 15 patients with subfoveal choroidal neovascularization secondary to AMD at a clinical unit for healthy participants and outpatient for patients with AMD.
  
  
  METHODS
  Oral pazopanib tablets, 5 to 30 mg daily (healthy participants) and 15 mg daily (patients with AMD).
  
  
  METHODS
  Safety, pharmacokinetics, best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29.
  
  
  RESULTS
  Oral pazopanib up to 30 mg daily in healthy participants and 15 mg daily in patients with AMD was well tolerated. Six of 15 patients received rescue therapy before day 29; all had the CFH Y402H CC "high-risk" genotype for AMD. Nine patients completed the study without rescue with improvements from baseline in best-corrected visual acuity (8 Early Treatment Diabetic Retinopathy Study letters), central retinal lesion thickness (-50.94 µm), and central retinal thickness (-50.28 µm). There was a trend for association between the CFH Y402H T allele ("low risk" for AMD, n = 6) and improvement.
  
  
  CONCLUSIONS
  Oral pazopanib (15 mg daily) was well tolerated and resulted in improvements in mean best-corrected visual acuity, central retinal lesion thickness, and central retinal thickness at day 29 in a per-protocol, nonrescued AMD population (n = 9). It is postulated that CFH Y402H genotype may help predict which patients respond to pazopanib. The size and length limitations of this study warrant further investigation to determine if oral pazopanib may be an appropriate treatment for a subset of neovascular patients with AMD or as an adjunct to standard of care.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01051700 and NCT01154062.
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Megan M
authors.initials: MM
authors.lastname: McLaughlin
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Marcella G
authors.initials: MG
authors.lastname: Paglione
authors.affiliation: Vitreous Retina Macula Consultants of New York, New York.
authors.forename: Jason
authors.initials: J
authors.lastname: Slakter
authors.affiliation: Center for Retina and Macular Disease, Winter Haven, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Tolentino
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.affiliation: GlaxoSmithKline, Stevenage, England.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016037:Single-Blind Method; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014792:Visual Acuity / Q000502:physiology; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; C493495:CFH protein, human; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D017242:Complement Factor H; D040262:Receptors, Vascular Endothelial Growth Factor